Endothelium-specific depletion of LRP1 improves glucose homeostasis through inducing osteocalcin

Nat Commun. 2021 Sep 6;12(1):5296. doi: 10.1038/s41467-021-25673-6.

Abstract

The vascular endothelium is present within metabolic organs and actively regulates energy metabolism. Here we show osteocalcin, recognized as a bone-secreted metabolic hormone, is expressed in mouse primary endothelial cells isolated from heart, lung and liver. In human osteocalcin promoter-driven green fluorescent protein transgenic mice, green fluorescent protein signals are enriched in endothelial cells lining aorta, small vessels and capillaries and abundant in aorta, skeletal muscle and eye of adult mice. The depletion of lipoprotein receptor-related protein 1 induces osteocalcin through a Forkhead box O -dependent pathway in endothelial cells. Whereas depletion of osteocalcin abolishes the glucose-lowering effect of low-density lipoprotein receptor-related protein 1 depletion, osteocalcin treatment normalizes hyperglycemia in multiple mouse models. Mechanistically, osteocalcin receptor-G protein-coupled receptor family C group 6 member A and insulin-like-growth-factor-1 receptor are in the same complex with osteocalcin and required for osteocalcin-promoted insulin signaling pathway. Therefore, our results reveal an endocrine/paracrine role of endothelial cells in regulating insulin sensitivity, which may have therapeutic implications in treating diabetes and insulin resistance through manipulating vascular endothelium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / pathology
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism
  • Gene Expression Regulation
  • Genes, Reporter
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Hyperglycemia / genetics*
  • Hyperglycemia / metabolism
  • Hyperglycemia / pathology
  • Insulin / metabolism
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Low Density Lipoprotein Receptor-Related Protein-1 / deficiency
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics*
  • Male
  • Mice
  • Mice, Knockout
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Osteocalcin / genetics*
  • Osteocalcin / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction

Substances

  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • GPRC6A protein, mouse
  • Igf1r protein, mouse
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • Receptors, G-Protein-Coupled
  • Osteocalcin
  • Green Fluorescent Proteins
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • Glucose